Effect of Salicylate on Glucose Metabolism in Insulin Resistance States

Data supports diet induced obesity leads to activation of the IKK/NF-kB inflamatory pathway and that chronic inflammation leads to insulin resistance and diabetes. In rodents, salicylates inhibit IKK/NF-kB and may improve insulin sensitivity. We will study if this is true in people.

Study Overview

• Status: Completed
• Conditions: Insulin Resistance
• Intervention / Treatment: Drug: Salsalate; Drug: Placebo

Detailed Description

Please see the following review articles on this topic:

Shoelson SE, Lee J, Goldfine AB. (2006) Inflammation in insulin resistance. J. Clin. Invest. 116, 1793-1801.

Goldfine AB, Fonseca V and Shoelson SE (2010) Therapeutic approaches to target inflammation in type 2 diabetes. Clin Chem. 57, 162-167.

Donath MY and Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 11, 98-107.

Goldfine AB and Shoelson SE (2017) Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk. J Clin Invest. 127, 83-93.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2; Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

age 18 to 65 years, inclusive; HbA1c >6.0% (off medication-diabetic) normal hemoglobin and hematocrit, without donation of blood in the previous 2 months; without involvement in any study evaluating an investigational drug or device for the previous 2 months; normal clotting studies; female postmenopausal or surgically sterile, or using barrier or oral contraception and with a negative pregnancy test.

Exclusion Criteria:

pregnant or lactating women; patients with persistent ketonuria or a history of ketoacidosis (suggesting the need for insulin therapy); current of previous use of insulin for glucose control; patients with abnormal liver function defined as elevation of bilirubin, alkaline phosphatase, ALT, AST, or GGTP more than 1.5 times the upper limit of normal; patients with kidney disease (serum creatinine > 1.5 mg/dL) macroalbuminuria (1+ protein on a standard urine dip-stick, or > 300 mg urinary albumin/day)- (patients with microalbuminuria will be enrolled); patients with any significant diseases or conditions, including emotional or psychiatric disorders and substance abuse, including history of binge drinking, that, in the opinion of the investigator, are likely to alter the patient's ability to complete the study; patients with metabolic acidosis (abnormal anion gap); history of gastric ulcer, dyspepsia, or upper or lower GI bleed; history of allergy to aspirin, or bleeding diathesis or currently on oral anticoagulants including warfarin, heparin, aspirin or other NSAIDs; patients with major vascular event within 6 months of screening for the study (e.g., myocardial infarction stroke, coronary artery bypass graft (CABG) surgery, angioplasty, peripheral vascular surgery); patients with chronic heart disease, or a history of myocardial infarction or stroke. Symptomatic angina pectoris or cardiac insufficiency as defined by the NYHA; classification as Functional Class III or IV; patients with HbA1C > 13% (normal range 4-6%); patients who smoke more than one pack of cigarettes daily; patients taking treatment medications known to affect insulin sensitivity (e.g. diuretics, beta-blockers); patients taking warfarin, heparin or NSAID on a chronic basis; patients with inadequately controlled serum lipid levels (total cholesterol ≥ 275 mg/dL and fasting triglycerides ≥ 450 mg/dL); patients with history of cancer within 5 years prior to screening for the study other than basal cell carcinoma; active alcohol or other substance abuse.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment; This third small study has a randomized, masked, placebo controlled parallel design to compare salsalate 4.0 g/d to placebo. This is the salsalate 4.0 g/d arm.	Drug: Salsalate; Active; Other Names: Disalcid
Placebo Comparator: Placebo; This third small study has a randomized, masked, placebo controlled parallel design to compare salsalate 4.0 g/d to placebo. This is the placebo arm.	Drug: Placebo; Placebo for salslate, used only in the third trial

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glucose	fasting glucose	4 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Adiponectin	4 weeks

Collaborators and Investigators

• Sponsor: Joslin Diabetes Center
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institutes of Health (NIH)
• Investigators: Principal Investigator: Steven Shoelson, Joslin Diabetes Center

Publications and helpful links

General Publications

• Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006 Jul;116(7):1793-801. doi: 10.1172/JCI29069. Erratum In: J Clin Invest. 2006 Aug;116(8):2308.
• Fleischman A, Shoelson SE, Bernier R, Goldfine AB. Salsalate improves glycemia and inflammatory parameters in obese young adults. Diabetes Care. 2008 Feb;31(2):289-94. doi: 10.2337/dc07-1338. Epub 2007 Oct 24.
• Goldfine AB, Silver R, Aldhahi W, Cai D, Tatro E, Lee J, Shoelson SE. Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes. Clin Transl Sci. 2008 May;1(1):36-43. doi: 10.1111/j.1752-8062.2008.00026.x.

Study record dates

Study Major Dates

• Study Start: January 1, 2000
• Primary Completion (Actual): May 1, 2008
• Study Completion (Actual): May 1, 2008

Study Registration Dates

• First Submitted: November 22, 2005
• First Submitted That Met QC Criteria: November 22, 2005
• First Posted (Estimate): November 24, 2005

Study Record Updates

• Last Update Posted (Actual): April 30, 2019
• Last Update Submitted That Met QC Criteria: April 8, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Insulin Resistance; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Salicylsalicylic acid
• Other Study ID Numbers: CHS 00-01; R37DK051729 (U.S. NIH Grant/Contract); R01DK051729 (U.S. NIH Grant/Contract)